Design, Synthesis, and Evaluation of Novel Δ2-Thiazolino 2-Pyridone Derivatives That Potentiate Isoniazid Activity in an Isoniazid-Resistant Mycobacterium tuberculosis Mutant

Souvik Sarkar, Anne E. Mayer Bridwell, James A.D. Good, Erin R. Wang, Samuel R. McKee, Joy Valenta, Gregory A. Harrison, Kelly N. Flentie, Frederick L. Henry, Torbjörn Wixe, Peter Demirel, Siva K. Vagolu, Jonathan Chatagnon, Arnaud Machelart, Priscille Brodin, Tone Tønjum, Christina L. Stallings, Fredrik Almqvist

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Mycobacterium tuberculosis (Mtb) drug resistance poses an alarming threat to global tuberculosis control. We previously reported that C10, a ring-fused thiazolo-2-pyridone, inhibits Mtb respiration, blocks biofilm formation, and restores the activity of the antibiotic isoniazid (INH) in INH-resistant Mtb isolates. This discovery revealed a new strategy to address INH resistance. Expanding upon this strategy, we identified C10 analogues with improved potency and drug-like properties. By exploring three heterocycle spacers (oxadiazole, 1,2,3-triazole, and isoxazole) on the ring-fused thiazolo-2-pyridone scaffold, we identified two novel isoxazoles, 17h and 17j. 17h and 17j inhibited Mtb respiration and biofilm formation more potently with a broader therapeutic window, were better potentiators of INH-mediated inhibition of an INH-resistant Mtb mutant, and more effectively inhibited intracellular Mtb replication than C10. The (−)17j enantiomer showed further enhanced activity compared to its enantiomer and the 17j racemic mixture. Our potent second-generation C10 analogues offer promise for therapeutic development against drug-resistant Mtb.

Original languageEnglish
Pages (from-to)11056-11077
Number of pages22
JournalJournal of Medicinal Chemistry
Volume66
Issue number16
DOIs
StatePublished - Aug 24 2023

Fingerprint

Dive into the research topics of 'Design, Synthesis, and Evaluation of Novel Δ2-Thiazolino 2-Pyridone Derivatives That Potentiate Isoniazid Activity in an Isoniazid-Resistant Mycobacterium tuberculosis Mutant'. Together they form a unique fingerprint.

Cite this